Most adult organs contain populations of slowly cycling, undifferentiated stem cells. Aside from maintaining their own numbers, stem cells produce progeny that differentiate into the various cell types of the organ they are located in. Adult stem cells are under intensive study with the goal in mind to use these cells in regenerative medicine. Furthermore, it has become clear that neoplastic growth typically takes off from stem cells or their proliferating progeny. One important population of adult stem cells are the epithelial stem cells of the intestine. We recently found in the Drosophila adult hindgut a stem cell system that shows a high degree of similarity to the mammalian intestinal stem cells, but at the same time is considerably simpler to analyze genetically and developmentally. Drosophila hindgut stem cells are confined to a short segment of the hindgut, the hindgut proliferation zone (HPZ). Within the HPZ, self renewal, proliferation and differentiation is controlled by local sources of four signaling pathways, the Wnt/Wingless, Hedgehog, Notch and Jak/Stat pathway. In the proposed project we will address some fundamental properties of the HPZ: what are the functional relationships between these pathways, and what aspect of stem cell behavior (cell cycle? adhesion? migration? pluripotency?) does each of them control? Furthermore, the rapid development and relative simplicity of the Drosophila intestinal tract gives us the opportunity to investigate when and how the HPZ with its special signaling properties during development. Finally, we want to screen for novel genes involved in adult stem cell proliferation. Our overall goal is to advance the knowledge of the fly HPZ system to a degree that makes it possible to formulate additional, specific and readily translatable research programs, using the fly hindgut stem cells as a model system.